What are highly potent active pharmaceutical ingredients (HPAPIs)?
Highly potent active pharmaceutical ingredients (HPAPIs) are the compounds used extensively today for the treatment of respiratory disorders, cancer and hormonal imbalances. The key factors driving the demand for highly potent active pharmaceutical ingredients (HPAPIs) are the rise in the oncology therapeutics market as well as the surge in the need for better medicines for treating Cardiovascular, Central Nervous System, Hormonal, Eye, Infectious, Metabolic and Inflammatory diseases.
A growing number of approved pharmaceutical drugs contain high-potency active pharmaceutical ingredients (HPAPIs), which has led to an explosive growth in demand for the production of HPAPIs using state of the art development methods of Highly Active Pharmaceutical Ingredients (HAPI) whilst adhering to cGMP guidelines. Another reason why the demand for HPAPIs is thriving is because of advances in clinical pharmacology. There is particular interest in HPAPI–antibody conjugate technology, which uses monoclonal antibodies to selectively deliver HPAPIs to specific cancer tumors. When conjugated to the antibody, the HPAPI targets cancer cells specifically and thereby spares non-target cells many of the toxic effects. One of the earliest examples is Mylotarg (gemtuzumab ozogamicin), which is commercialized for treating acute myeloid leukemia.
Although this emerging market is attractive, it presents a significant challenge for pharmaceutical manufacturers to upgrade existing facilities that are set up to handle only non-potent APIs—the challenge being the major cost associated with the specialized containment needed to ensure that employees and their environment are protected from exposure. Many contract manufacturers are also building new facilities that are designed specifically for the manufacture of HPAPIs, which require an investment of millions of dollars beyond typical GMP (good manufacturing practices) production facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate both handling of high potent APIs and biologics processing capabilities.
Highly active or potent pharmaceutical ingredients (HPAPIs) comprise different compounds, but share one deadly characteristic: the potential to inhibit production of specific enzymes and cause cancer, mutations, development effects, or sickness, at very low doses, in those exposed to them. While there is an upsurge in the number of types of HPAPIs, it is important to keep in mind the essential attributes of HPAPIs. Drug manufacturers are developing more potent drugs, and despite the lack of specific environmental and safety regulations, HPAPIs have become fertile ground for contract manufacturing and contract development and manufacturing organizations (CMOs and CDMOs), which have been actively building up capacity over the past few years. Experts warn, however, that a systematic and scientific approach is needed. Simply having containment equipment and basic procedures will not be enough to ensure safety.
Typically, large pharmaceutical companies have the industrial hygienists and occupational toxicologists on staff to evaluate the potential risks of any new HPAPI, and to conduct the necessary safety assessments. Smaller companies and CDMOs/CMOs may not have those experts on staff. Teams that visit potential contract partners may be so focused on cGMPs and product specs that they overlook questions of worker safety and environmental risk from exposure to HPAPIs.
In addition, CDMOs/CMOs may not have done a sufficiently thorough assessment to determine whether they can handle a potent new drug safely. Failure to vet potential partners thoroughly can lead to regulatory problems with the Occupational Health and Safety Administration (OSHA), United States and potential legal liability. The APIs deemed to be potent fall into one of the 4 important categories:
1. A pharmacologically active ingredient or intermediate with biological activity at approximately 150 ?g/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg).
2. A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses.
3. An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 ?g/m3 of air as an 8-h time-weighted average.
4. The potency of pharmaceutical chemicals is often characterized by OELs in ?g/m3; the lower the value, the more potent the chemical and the greater the level of containment that is required, hence, by default, a novel compound of unknown potency and toxicity is often considered as an HPAPI.
Currently, there is a significant increase in the number of APIs going through development and clinical trials, and into the production environment with OELs much below 10 ?g/m3. These processes require specialized containment to ensure that employees and their environment are protected from exposure. Considering a basic facility design of a typical kilo-laboratory (using glassware for HPAPI handling), the main features of handling of High Potent APIs are as follows:
1. Room pressure differentials designed for containment (with monitoring and verification), with the main HPAPI-handling area at negative pressure to surrounding rooms
2. Airlocks and vestibules around manufacturing and laboratory spaces to provide gowning and de-gowning areas and proper pressure differentials
3. Restricted access to ensure that only the necessary trained employees enter the HPAPI-handling areas
4. HVAC (heating, ventilation, and air conditioning) systems designed for single-pass air—no return, with temperature, humidity, and particulate controls
5. Misting showers as part of de-gown and exit vestibules to rinse personal protective equipment (PPE) and gowning prior to removal
6. Filtration and capture of contaminants, with safe-change filters, both point source (within the isolator, ventilated enclosure) and the general HVAC exhaust system
7. Preventive maintenance and change-control procedures should be present to ensure that equipment and systems continue to operate properly and according to design specifications.
The global HPAPI market is broadly classified as Innovative HPAPI and Generic HPAPI based on customer base. Based on business type, the market is classified into Captive HPAPI & Merchant HPAPI. HPAPI market is segmented on the basis of molecule type as Synthetic HPAPI and Biotech HPAPI. HPAPI market application segment is classified into Oncology, Cardiovascular, Central Nervous System, Hormonal, and Eye diseases, Infectious, metabolic, Inflammation and other therapeutic applications.
Among Innovative & generic HPAPI, Innovative HPAPI occupies the major share during 2016 and generic HPAPIs expected to grow at a highest CAGR from 2016 to 2023. Among business type, Captive HPAPI occupies the major share during 2016 and Merchant HPAPI is expected to grow at a highest CAGR from 2016 to 2023. Among molecule type, Synthetic HPAPI occupied the major share during 2016 and is expected to grow at high single digit CAGR from 2016 to 2023 to reach $17,434.4 million by 2023. Among Application segment, Oncology commanded the larger revenue in 2016 and is expected to grow at highest CAGR from 2016 to 2023.
Increasing incidence of chronic and age-related diseases, rapid growth in oncology market, growing demand for Antibody Drug Conjugates (ADC), technological advancements in HPAPI market, growing CMOs are some of the factors which are driving the market. Requirement of large investments, stringent safety and handling specifications associated with production of HPAPI, stringent regulations are the factors hindering the market.
North America accounts for the highest market share in 2016 followed by Europe. However, Asian countries especially China and India are the fastest growing regions with demand for highly potent API for pre-clinical trials & commercial use. Asia-Pacific is projected to grow with a highest CAGR from 2016 to 2023. High potency active pharmaceutical ingredients (HPAPIs) market is a growing concept and is considered to be a boost to the pharmaceutical industry. Patented high potency drug development majorly dominates the HPAPI market. The branded sector constitutes the major share of this market but the patents of this branded sector are expected to expire in the coming few years that will help HPAPI manufacturers (HPAPI CMOs) to cater to multiple clients by producing the generic version of the ingredients in bulk.
The other key factor for rapid growth rate is that the majority of blockbuster drugs are nearing patent expiry ad that puts the US government in a position to promote generic drugs to reduce its medical burden. This leads to insurance companies preferring generic drugs over patented drugs for cost effectiveness, while India and China became the hub of HPAPI development through state of the art facilities (HPAPI CMOs) and demand with maximum DMFs with the US FDA.
The key drivers of growth and the reasons for visible opportunities:
• Increasing Incidence of Chronic and Age Related Diseases
• Rapid Growth in Oncology Market
• Growing Demand for Antibody Drug Conjugates (ADCs)
• Technological Advancements in HPAPI Market
• Growing HPAPI CMOs (Contract Manufacturing Organizations) Market
• Restraints and Threats
Threats and future scope of factors to consider with respect to investments and regulatory filings include:
• Requirement of Large Investment
• Stringent Safety and Handling Specifications Associated With the Production of HPAPI
• Stringent Regulations
• Alternative Therapies to Cure the Cancer
Here we also present a partial list of companies working on HPAPI development and scale up operations, globally as follows:
• Abbott Laboratories
• Abbvie Contract Manufacturing
• Adc Biotechnology
• Adc Therapeutics
• Aenova Group Gmbh
• Agno Pharma
• Ajinomoto (Althea Inc.)
• Alcami Corporation
• Alkermes Plc
• Almac Group
• Ampac Fine Chemicals
• Amri Global
• Anvi Pharma
• Asymchem Laboratories
• Avanthera S.A.
• Avara Pharmaceutical Services
• Axcellerate Pharma Services
• Baxter International
• Biocon Limited
• Biopharma Technology
• Biophore India Pharmaceuticals Pvt. Ltd
• Boehringer Ingelheim
• Bristol-Myers Squibb
• Bryllan Llc
• Buchiglas-Usa Corp.
• Cambrex Corporation
• Catalent Pharma Solutions Inc
• Celgene Biotechnology
• Cerbios Pharma Sa
• Chemigran Pte Ltd.
• Consort Medical
• Custom Processing Services Inc
• Dalton Pharma Services
• Dec-Usa Inc.
• Dishman Group
• Dottikon Exclusive Synthesis
• Dr. Reddy's Laboratories
• Emcure Pharmaceuticals
• Esteve Quimica
• Eurofins Scientific
• Evonik Industries
• Evotec A.G.
• Farhispania Group
• Ferro Corporation
• Formosa Laboratories Inc.
• Fresenius Kabi
• Gp Pharm
• Helsin Advanced Synthesis.
• Hikal Limited
• Hikma Pharmaceuticals
• Icrom S.P.A
• Idifarma Pharmaceutical Development S.L.
• Intas Biopharmaceuticals
• International Chemical Investors S. E
• Johnson Matthey
• Kyongbo Pharmaceutical Co. Ltd
• Laurus Synthesis Inc
• Lonza Group
• Lupin Limited
• Mayne Pharma (Libertas Pharma Inc)
• Merck KGaA
• Mersana Therapeutics Inc.
• Minakem High Potent
• Mitsubishi Tanabe Pharma Corp.
• Natco Pharma
• Neuland Health Sciences Private Limited
• Novasep Holding Sas
• Olon S.P.A.
• Opko Health
• Oso Biopharmaceuticals Manufacturing Llc
• Pierre Fabre
• Piramal Pharma Solution
• Powder Systems Limited
• Procos S.P.A
• Project Pharmaceutics
• Qs Pharma Llc
• R-Pharm Germany Gmbh.
• Regis Technologies Inc.
• Scinopharm Taiwan Limited
• Seattle Genetics Inc.
• Seigried Holding
• Servier Cdmo
• Shilpa Medicare
• Stason Pharmaceuticals
• Strides Arcolabs
• Sundia Meditech
• Symbiosis Pharmaceutical Services
• Syntagon Ab
• Synthon Biopharmaceuticals
• Teva Pharmaceutical Industries
• Thermofisher Scientific (Patheon N.V.)
• Uman Pharma
• Umicore N.V.
• Vion Pharmaceuticals, Inc
• Vxp Pharma Services
• Wuxi Pharmatec
• Yprotech Limited
High-Potency APIs: Containment and Handling Issues
While selecting the ultimate HPAPI development and/or HPAPI manufacturing partner, it is important that you select a company that has expertise in HPAPI containment and handling Issues. The CMO or CDMO partner you choose for HPAPI development, characterization and testing should have cleaning abilities, decontamination, and product changeover methods in place. They should be able to control employee activity in the facility to minimize exposure potential and offer flexibility (i.e., check whether the facility design allows easy reconfiguration?).
Operating an HPAPI manufacturing facility means that a number of systems, policies, and standard operating procedures (SOPs) must be put in place to protect staff and equipment. Additionally, manufacturers must ensure all employees handling High Potent APIs are adequately trained. Senior management must support the implementation of such systems, which includes providing the necessary funding for these systems. There should be regular reviews of material safety data sheets, toxicological literature, and relevant occupational safety and health literature for knowledge regarding the compounds used. These reviews should also include information on PPE and engineering processes.
It is vital that HPAPI-handling systems and equipment are tested and verified to meet the necessary isolation requirements. For example, isolation equipment may be expected to meet a containment capability of less than 1 ?g/m3. The capability of equipment, systems, and procedures to contain and isolate materials under expected operating conditions must be verified in a High Potency lab as a critical component of the overall HPAPI handling program.
This process typically requires the use of both air and surface industrial hygiene sampling methods to confirm proper isolation following a detailed sampling plan. In many cases, sampling and testing methods for products in early preclinical or clinical testing have not been developed. Therefore, surrogate products such as lactose or naproxen sodium, are frequently used to complete the equipment testing for conducting efficient HPAPI containment checks, and perform audit checks on documents involved in manufacturing high potency drugs using isolators.
A bio-decontaminated environment
The automatic cycle of bio-decontamination guarantees the reproducibility of the process. Manual disinfection is a time-consuming activity that may not be consistently performed and is dangerous because of the continuous exposure of operators to sanitizing agents. Bio-decontaminating agents such as vaporized hydrogen peroxide achieve sterilization by the dispersion of gas. The gas can reach all surfaces exposed to its contact, even the hidden ones. Its products are oxygen and water, which are harmless. Iso-techniques also exceed the onerous barrier created by the modality of clothing and microbiological control. The US Food and Drug Administration has expressed a favorable opinion for increasing the use of iso-techniques for drug production in asepsis, especially for the production of high-potency APIs.
Isolators for high-potency drugs
Some aspects to consider when using isolators while processing injectable, high-potency drugs are:
• Containment of contamination, particularly airborne contamination
• Individual protection of personnel
• Management of cross-contamination
• Aseptic processing and sterility of handled material and product
• Efficiency of bio-decontamination cycles
• Efficiency of barriers and their integrity
• Management of the environmental impact as a result of the process (i.e., refluent, industrial waste, liquids, gas, and air).
A practical demonstration of the productions of liquids or lyophilized injectables in glass vials is shown in Figure 1. The operating line is set up by several isolators partly connected in a row, where all manufacturing operations are done. These operations are: weighing of raw materials, their volatilization in tanks, transfer of the solution to the dosage systems, washing and depyrogenation of vials, filling of vials, capping (complete if liquid; partially, if liquids are to lyophilize), eventual freeze-drying, sealing, external washing, and drying of filled and sealed vials. The process is made in a production line with isolators. The following are phases of the main production process:
Phase I: Preparation of the distribution circuit (distributor, needles, and tubes)
Phase II: Preparation of isolators (cleaning and biodecontamination)
Phase III: Preparation of various materials (vials, stoppers, and seals)
Phase IV: Preparation of the solution and its filtration.
Phase II is typically for a production process using isotechniques. Phase IV is strongly affected by the kind of API (i.e., high-potency) used in the solution preparation and this aspect considerably changes the manipulation modalities of the API.
Treating circulating air. Depending on the phase of the manufacturing process, the surroundings of isolators may be in depression (i.e., when the drug is a powder, but not yet sterile, and is highly dangerous because of its aerosol dispersion) or in overpressure (i.e., when the aseptic processing becomes the most critical element).
The air that is poured into the isolators of degree 100 is subject to absolute filtering. The air taken by isolators is partly expelled in the environment and partly recycled with an input of fresh air from the ambient environment. The amount of air subject to recirculation is treated by filtration using high-efficiency particulate air (HEPA) filters, HEPA filter efficiency classification H13 (i.e., recovery), and afterward by a H13 filter (expulsion). In these isolators, the product can be present only in liquid form and only because of accidental reversal or vials that are not well closed. Therefore, the aerosol contamination is near to zero.
In case of isolator compounding, the exhaust air is treated by a H14 filter (i.e., HEPA filter efficiency classification H14). The retaken one is a totally recycled previous filtration by a H14 filter with the use of a further intermediate H13 filter.
It is believed that a promising pipeline of targeted therapeutic drugs will help the HPAPI market progress in the coming years. HPAPI drugs have minimal side effects and impact targeted areas, thereby helping the patient to recover faster with no lingering after effects. The development of HPAPIs has a key driver in the growth of oncology drugs which have shown the maximum demand in the last few years until 2018. The oncology drugs segment has been the leading segment of the global high potency active pharmaceutical ingredient market.
The introduction of innovative drugs is the primary growth driver for the oncology segment. Analysts predict that the patent expiry of blockbuster drugs such as Herceptin, Rituxan, and Humira will pave the way for generic drug manufacturers, thereby making these drugs affordable to a wide number of patients.
Positive perceptions surrounding HPAPIs combined with the near-expiration dates of blockbuster drugs, which will offer several generic drug manufacturers a chance to offer affordable drugs, will further the market’s growth. Consistent research and development to mimic branded drugs will create alternative and cost-effective treatments for patients across the globe, thereby augmenting the growth rate of the market.